The four serotypes of dengue virus (a mosquito-born flavivirus) cause an acute febrile illness that occasionally results in hospitalization for treatment of hemorrhage (dengue fever, DF) or hemorrhage plus plasma leakage resulting in hypovolemia (dengue hemorrhagic fever; DHF). Hospitalization for these complications usually occurs during a second heterotypic infection, suggesting a role for dengue antibodies in pathogenesis. The major antigen of the virus, against which neutralizing, hemagglutination-inhibiting, and flavivirus cross-reactive antibodies are directed, is the envelope glycoprotein (E). Computer analysis revealed a 20 residue region of similarity in amino acid sequence between the dengue type 4 E and a family of clotting factors, including plasminogen, the prime mediator of fibrinolysis. Using synthetic peptides in ELISA, E antibodies that potentially bind plasminogen were previously detected in 75% of 40 Thai patients acutely infected with dengue virus type 1, 2, 3, or 4. Plasminogen cross-reactivity of dengue antibodies was shown to be specific for the related sites in E and plasminogen. The dengue E sequence with similarity to plasminogen is largely conserved within the currently known flavivirus E sequences. However, 15 Thai patients hospitalized for illness caused by Japanese encephalitis (JE) virus (a flavivirus not associated with hemorrhage) did not develop plasminogen cross-reactive antibodies, and this finding correlated with failure of JE antibodies to bind to the plasminogen cross-reactive site in E. An in vitro assay was developed to evaluate the possible effect of plasminogen cross-reactive antibodies in sera from dengue virus infected patients on plasmin activity in the presence or absence of alpha2-antiplasmin, the naturally occurring plasmin antagonist. Preliminary results show that such antibodies have a minimal inhibitory effect on plasmin activity that is synergistically augmented in the presence of alpha2-antiplasmin.